REGULATION OF LYMPHOCYTE METABOLISM AND HOMEOSTATIS BY THE C-MYC/AP4 AXIS

 描述（由申请人提供）：对病原体的免疫应答需要淋巴细胞协调其激活的两个时间上不同的阶段。在抗原（Ag）相遇时，B和T细胞启动活化，该程序涉及基因表达、蛋白质合成和碳水化合物代谢的动态增加。在起始阶段之后，必须维持活化程序以完成克隆扩增并产生有效病原体清除所需的Ag特异性淋巴细胞的数量。转录因子cMyc在淋巴细胞活化的起始阶段起重要作用。然而，我们的数据表明，cMyc表达并不持续在整个T细胞反应期间。这一结果表明，其他转录因子可能取代cMyc表达的损失，以维持淋巴细胞增殖。我们发现，cMyc诱导的转录因子，AP4，是一个关键的细胞内在调节CD8 T淋巴细胞增殖在后Myc阶段。AP4是许多cMyc靶基因通过其直接结合到假定的调控元件而持续转录所必需的，并且对于CD8 T细胞针对病毒感染的保护性免疫是必需的。在这项研究中，我们将研究两种转录因子在免疫反应中的时间调节要求的生物学意义，这些免疫反应可能平衡正常的淋巴细胞增殖和预防淋巴瘤。

 DESCRIPTION (provided by applicant): Immune responses to pathogens require lymphocytes to orchestrate two temporally distinct phases of their activation. Upon antigen (Ag) encounter, B and T cells initiate activation, a program involving dynamic increases in gene expression, protein synthesis, and carbohydrate metabolism. Following the initiation phase, activation programs must be maintained to complete clonal expansion and generate the numbers of Ag- specific lymphocytes required for efficient pathogen clearance. The transcription factor cMyc plays an essential role in the initiation phase of lymphocyte activation. However, our data show that cMyc expression does not persist during the entire period of T cell responses. This result suggests that other transcription factors may substitute the loss of cMyc expression to maintain lymphocyte proliferation. We discovered that a cMyc- inducible transcription factor, AP4, is a critical cell-intrinsic regulator of CD8 T lymphocyte proliferation during the post-Myc phase. AP4 is required for continued transcription of many cMyc target genes via its direct binding to presumed regulatory elements and essential for protective immunity by CD8 T cells against viral infection. In this grant, we will study the biological significance of the temporally regulated requirements of the two transcription factors in immune responses that may balance normal lymphocyte proliferation and prevention of lymphomagenesis.